CN101780039A - Tramadol multivesicular liposome and preparation method thereof - Google Patents
Tramadol multivesicular liposome and preparation method thereof Download PDFInfo
- Publication number
- CN101780039A CN101780039A CN 201010118394 CN201010118394A CN101780039A CN 101780039 A CN101780039 A CN 101780039A CN 201010118394 CN201010118394 CN 201010118394 CN 201010118394 A CN201010118394 A CN 201010118394A CN 101780039 A CN101780039 A CN 101780039A
- Authority
- CN
- China
- Prior art keywords
- tramadol
- water
- phospholipid
- liposome
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a tramadol multivesicular liposome and a preparation method thereof. The preparation method comprises the following steps of: 1, dissolving phospholipids, cholesterol and neutral lipids into organic solvents to obtain a mixture which serves as an organic phase; 2, preparing 10 to 500mmol/L tramadol solution which serves as an internal water phase; 3, adding the internal water phase with the same volume as that of an organic phase into the organic phase, and mixing and emulsifying the mixture to obtain water-in-oil primary emulsion; 4, preparing an external water phase containing amino acid and osmotic modulators and/or surfactants, and adding the external water phase of which the volume is 2 to 10 times that of the water-in-oil primary emulsion into the water-in-oil primary emulsion, stirring the mixture to form oil-in-water type double emulsion; 5, adding the emulsion into the solution of the amino acid, introducing nitrogen or carbon dioxide into the mixed solution to remove the organic solvent from the emulsion to obtain suspension; 6, dissolving the suspension into the solution of amino acid, centrifuging and taking lower liposome suspension to obtain the tramadol multivesicular liposome. The prepared tramadol multivesicular liposome has the advantages of higher encapsulation efficiency, good slow release effect, and longer analgesic effect.
Description
Technical field:
The present invention relates to slow release liposome ejection preparation of a kind of tramadol and preparation method thereof, particularly a kind of tramadol multivesicular liposome and preparation method thereof.
Background technology:
Tramadol (Tramadol) is the central opioid analgesic, has two different mechanism of action that replenish mutually: the μ receptor is had weak affinity, be about 1/6000 of morphine; The reuptake that in central nervous system (CNS) pain pathways, suppresses norepinephrine and 5-hydroxy tryptamine simultaneously.Its O-demethyl metabolite (M1) also has analgesic activity, to the affinity of μ receptor 200 times of parent, the analgesia intensity of tramadol is when Isodose, be equivalent to 1/5 of morphine, single oral dose tramadol 37.5mg, blood drug level reached peak value after 1.8 hours, the peak value of dextrorotation and left-handed tramadol hydrochloride blood drug level is respectively 64.3ng/ml and 55.5ng/ml.Present clinical moderate and severe pain patient, mainly the analgesic that uses is opioid drug.Most patient wishes to reduce as far as possible administration number of times, and in some cases, as perform the operation back or old patient, oral administration can not satisfy the requirement of dosage regimen, therefore need make slow-release injection, the moderate safety range height of tramadol dosage is fit to make slow releasing preparation.
Kim (Biochim Biophys Acta, 1983,728 (3)) adopt multi-emulsion method to be prepared into many vesicles liposome (Multivesicular Liposomes at first, MVLs), studies show that MVL inside is to be made of with non-concentrically ringed form many aqueous chambers, be separated by with lipid bilayer between each aqueous chamber, neutral lipid is distributed in the interface point place of adjacent aqueous chamber as holder, forms firm topological structure, and its particle diameter is generally 5～50 μ m.The height that traditional liposomal generally is difficult to reach water soluble drug with prior art is sealed and is hanged down seepage, many vesicles liposome has numerous advantages such as envelop rate height, envelope volume is big, drug leakage is few by comparison, is particularly useful for sealing soluble small molecular and bioactive macromolecule medicine.Because of its non-concentrically ringed topological structure, make multivesicular liposomes form medicine " bank " in the injection site, along with the continuous metabolism of phospholipid bilayer, the medicine that is encapsulated in the vesicle progressively is released into blood or diseased region, and performance well postpones release action.By regulating parameter and the prescription ratio in the preparation process, can the control drug release time within these few days.
Yet, the problem that exists is at present: because different active constituents of medicine has the different physicochemical properties and the mechanism of action, its preparation envelop rate and drug release have than big-difference, therefore at concrete medicine and release request thereof, need research to adopt specific prescription and technology.
Summary of the invention:
The technical problem to be solved in the present invention is above-mentioned problem, and a kind of preparation method with tramadol multivesicular liposome of slow releasing function is provided, and technological parameter in this preparation method and prescription ratio are selected rationally, the entrapment efficiency of preparation and had good sustained release effect.This purpose realizes by following steps:
1. phospholipid, cholesterol, the neutral lipid with natural or synthetic is dissolved in the organic solvent, as organic facies, wherein the molar concentration of phospholipid in organic facies is 5～50mmol/L, the molar concentration of neutral lipid in organic facies is 1～10mmol/L, and the mol ratio of phospholipid and cholesterol is 1: 2～4: 1;
2. be 10～500mmol/L with tramadol its concentration that makes soluble in water, as interior water;
3. water in the 2. middle gained of step is added in isopyknic organic facies, shear-mixed emulsifying makes the water-in-oil type colostrum;
4. dispose the Freamine of 1～100mmol/L, in the Freamine that configures, add surfactant that 0.1～9% the osmotic pressure account for its weight regulates material and/or 0.01%～10% as outside water, outer water is added the 3. first Ruzhong of water-in-oil type of middle preparation of step, mix and form W/O/W type emulsion, be W/O/W type emulsion, the volume ratio of wherein said outer water and water-in-oil type colostrum is 1: 1～10: 1;
5. the W/O/W type emulsion that obtains is added in the 4. middle Freamine that disposes of step, wherein the volume ratio of W/O/W type emulsion and Freamine is 3: 1～1: 3, feed nitrogen or carbon dioxide and dry up the organic solvent of removing in the emulsion, obtain the suspension of liposome;
6. the suspension of liposome is dissolved in 1～100 times of volume step 4. in the Freamine of configuration, centrifugal treating then, the supernatant that inclines is collected lower floor's liposome turbid liquor, tramadol multivesicular liposome.
Wherein, step 1. described in phospholipid be selected from lecithin, soybean phospholipid, hydrolecithin, dimyristoyl phosphatidyl choline, PHOSPHATIDYL ETHANOLAMINE, DOPE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidyl glycerols, the phosphatidyl glycerol one or more, one or more in preferred hydrolecithin, soybean phospholipid, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, the two palmityl phosphatidyl glycerols; Neutral lipid is selected from one or more in olein, glycerol trioleate, glyceryl laurate ester, decanoin, tricaprylin, 3-butyrine glyceride, the vitamin E, preferred glycerol trioleate; Organic solvent is selected from one or more in ether, chloroform, dichloromethane, ethanol, butanols, oxolane, the ethyl acetate, preferred chloroform or ether-dichloromethane mixture, wherein the volume ratio of ether and dichloromethane is 1: 3～3: 1 in the ether dichloromethane mixture; The aminoacid of step described in 4. is a kind of in L-arginine, L-lysine, serine or the Aspartic Acid, osmotic pressure adjusting material is one or more in glucose, mannitol or the sodium chloride, preferred sodium chloride and/or glucose, surfactant is one or more in Tween 80, span 20 or the polyvinyl alcohol.
The lipoid that can also contain electronegative or positive charge in this step organic facies 1., electrically charged lipoid can effectively be regulated the surface of liposome electric charge, makes the electronegative or positive electricity of liposome, to strengthen preparation stability.The weight ratio of this lipoid and middle phospholipid can be 1: 1～and 1: 50, preferred 1: 3～1: 20 of the present invention.Tramadol dissolubility in water is higher, and it is acid that pH value of water solution shows, and more helps sealing of tramadol when surface of liposome is electronegative, thereby improves the envelop rate of tramadol liposome.Therefore one or more in the electronegative lipoid such as the preferred Phosphatidylserine of lipoid of the present invention, phosphatidic acid or 18-amine..
Above-mentioned steps 3. described in mixing and emulsifying can adopt prior art, as handling by apparatus and method such as stirring, vibration, supersound process, dispersing emulsification machines; The present invention preferably adopts high speed dispersing emulsification machine and ultrasonic.
And above-mentioned steps mix to form emulsion and the step organic solvent method of removing in 5. in 4. and all can adopt prior art, remove wherein that the organic solvent method includes but are not limited to that air-flow dries up, reduction vaporization etc., usually select for use gases such as nitrogen, carbon dioxide to remove organic solvent, commonly used is nitrogen.
Another object of the present invention provides a kind of tramadol multivesicular liposome, and it is to be made by above-mentioned preparation method.
Beneficial effect of the present invention:
1, in phospholipid, adds cholesterol, can produce following influence: increase liposome stability in vivo, the difficult drug leakage of breaking liposome property; Reduce the permeability of water soluble molecules to the liposome adipose membrane; Increase the stability of liposome, prolong the time in blood circulation.
2, relative traditional liposomal has added a kind of neutral lipid in the lipid components of many vesicles liposome, as glycerol trioleate, and tricaprylin, 3-butyrine glyceride.The neutral lipid that is added does not have film forming ability, but it can be filled in the hydrophobic space in the lipid bilayer, stablize the connection of infall, form discontinuous drug solution vesicle after making the liposomal encapsulated medicine of many vesicles, so neutral lipid is one of deciding factor that forms many bubble (many capsules) liposomees.
3, can also contain the lipoid of electronegative or positive charge in the interior aqueous phase lipid components of this liposome, electrically charged lipoid can effectively be regulated the surface of liposome electric charge, makes the electronegative or positive electricity of liposome, to strengthen preparation stability.Tramadol dissolubility in water is higher, and it is acid that pH value of water solution shows, and more helps sealing of tramadol when surface of liposome is electronegative, thereby improves the envelop rate of tramadol liposome.
4, tramadol multivesicular liposome of the present invention has high envelop rate, and in vivo, all show the good slow release effect in the in vitro tests, thereby existing preparation has better analgesic effect, and has reduced medication number of times and total dosage thus.
Description of drawings:
Fig. 1 is the release in vitro-time plot of tramadol multivesicular liposome of the present invention.
The specific embodiment:
Further specify the present invention with embodiment below, but the present invention is not limited.
The tramadol multivesicular liposome particle diameter adopts laser light scattering instrument to detect among the following embodiment; The entrapment efficiency determination method is:
Get many vesicles liposome turbid liquor 5ml, the centrifugal 30min of 4000r/min.Get supernatant, with 0.22 μ m filtering with microporous membrane, after the dilution, the HPLC method is measured the content of free tramadol; Other gets many vesicles liposome turbid liquor 1ml, adds 5%Triton X-100 alcoholic solution 1ml, puts the 10min that vibrates on the agitator, the film material is broken fully, filter, it is an amount of to get subsequent filtrate, after the dilution, measure the total amount of tramadol in the suspension, according to following formula computational envelope rate.
Envelop rate=(1-W free/W is total) * 100%
Embodiment 1
1. take by weighing soybean phospholipid 50 μ mol in proportion, dioleoyl phospholipid phatidylcholine (DOPC) 80 μ mol, two palmityl phosphatidyl glycerols (DPPG), 50 μ mol, cholesterol (CH) 100 μ mol, glycerol trioleate (To) 12 μ mol, place volumetric flask, add chloroform 5ml it is dissolved fully, become organic facies;
2. compound concentration is the tramadol hydrochloride solution 5ml of 500mmol/L, as interior water;
3. water 5ml slowly splashes among the organic facies 5ml of step 1 in getting, mixing and emulsifying and ultrasonic 5min, and the colostrum of one-tenth water-in-oil type (W/O) is viewed as the translucent viscous liquid of milky;
4. preparation contains 3% glucose, 0.2% span 20, and molar concentration is the outer water of arginic solution conduct of 40mmol/L, injects water outside the 25mL to the first Ruzhong of the W/O that makes, emulsifying and ultrasonic 5min get the emulsion of W/O/W type (W/O/W);
5. the emulsion of the W/O/W that makes is shifted and pour in the conical flask of 250ml, add the arginine 50ml of 40mmol/L, constant temperature feeds nitrogen to the solution bottom for 40 ℃, and concussion eliminates chloroform, gets liposome turbid liquor;
6. the L-lysine solution that adds the 20mmol/L of 100ml dilutes many vesicles liposome turbid liquor, leaves heart 10min with 3000, and the supernatant that inclines is isolated liposome turbid liquor, removes outer aqueous phase free drug, must tramadol multivesicular liposome.
Recording the tramadol multivesicular liposome particle diameter is 1～50 μ m; Envelop rate is 78～85%.
Embodiment 2
1. take by weighing hydrogenated soya phosphatide 80 μ mol in proportion, dioleoyl phospholipid phatidylcholine (DOPC) 50 μ mol, two palmityl phosphatidyl glycerols (DPPG), 200 μ mol, cholesterol (CH) 120 μ mol, glycerol trioleate (To) 10 μ mol, place volumetric flask, add ether: chloroform (volume ratio 1: 1) 5ml dissolves it fully, becomes organic facies;
2. the preparation molar concentration is 10mmol/L tramadol hydrochloride solution 5ml, becomes interior water;
3. get above-mentioned interior water 5ml and slowly splash among the organic facies 5ml of step 1, mixing and emulsifying and ultrasonic 10min, the colostrum of one-tenth water-in-oil type (W/O) is viewed as the translucent viscous liquid of milky;
4. preparation contains 0.9% sodium chloride, 0.01% Tween 80, and molar concentration is the outer water of arginic solution conduct of 50mmol/L, water 25mL outside the first Ruzhong of the W/O that makes is injected, emulsifying and ultrasonic 5min get the emulsion of W/O/W type (W/O/W);
5. the emulsion of the W/O/W that makes is shifted and pour in the conical flask of 250ml, add 50mmol/L arginine solution 100ml, constant temperature feeds nitrogen to the solution bottom for 40 ℃, and concussion eliminates organic facies, gets liposome turbid liquor;
6. the 50mmol/L arginine solution that adds 250ml is diluted many vesicles liposome turbid liquor, leaves heart 10min with 3000, and the supernatant that inclines is isolated liposome turbid liquor, removes outer aqueous phase free drug, must tramadol multivesicular liposome.
Recording the tramadol multivesicular liposome particle diameter is 1～45 μ m; Envelop rate is 83～88%.
Embodiment 3
1. take by weighing lecithin 30 μ mol in proportion, DOPE 80 μ mol, two palmityl phosphatidyl glycerols, 50 μ mol, phosphatidyl glycerol 10 μ mol, cholesterol 30 μ mol, glycerol trioleate 12 μ mol, Phosphatidylserine 10 μ mol, phosphatidic acid 10 μ mol place volumetric flask, add chloroform 5ml it is dissolved fully, become organic facies.
2. compound concentration is the tramadol hydrochloride solution 5ml of 500mmol/L, as interior water.
3. water 5ml slowly splashes among the organic facies 5ml of step 1 in getting, mixing and emulsifying and ultrasonic 5min, and the colostrum of one-tenth water-in-oil type (W/O) is viewed as the translucent viscous liquid of milky;
4. preparation contains 3% mannitol, 0.1% polyvinyl alcohol, and molar concentration is the outer water of L-lysine solution conduct of 20mmol/L, injects water outside the 25mL to the first Ruzhong of the W/O that makes, emulsifying and ultrasonic 5min get the emulsion of W/O/W type (W/O/W);
5. the emulsion of the W/O/W that makes is shifted and pour in the conical flask of 250ml, add the L-lysine solution 50ml of 20mmol/L, constant temperature feeds nitrogen to the solution bottom for 40 ℃, and concussion eliminates chloroform, gets liposome turbid liquor.
6. the L-lysine solution that adds the 20mmol/L of 100ml dilutes many vesicles liposome turbid liquor, leaves heart 10min with 3000, and the supernatant that inclines is isolated liposome turbid liquor, removes outer aqueous phase free drug, must tramadol multivesicular liposome.
Recording the tramadol multivesicular liposome particle diameter is 1～35 μ m; Envelop rate is 81～89%.
Used lecithin is the goldschmidt chemical corporation product among the above embodiment; Dioleoyl phospholipid phatidylcholine, DOPE, Phosphatidylserine, phosphatidyl glycerol, phosphatidic acid and two brown paulownia acyl phosphatidyl glycerols are purchased the company in Sigma; Cholesterol is purchased new hundred pharmaceutical Co. Ltds in Nanjing; Glycerol trioleate is purchased in Chemical Reagent Co., Ltd., Sinopharm Group; All the other reagent are conventional commercially available prod.
Experimental example 1: the release in vitro of tramadol multivesicular liposome is measured
Get the tramadol multivesicular liposome suspension 20ml of embodiment 1, dilute with the 80ml normal saline, precision is measured tramadol multivesicular liposome suspension 3mL and is placed bag filter through pretreated 80,000 relative molecular weights, tighten, place the digestion instrument corbeil, adding the 900mL sodium chloride solution in the digestion instrument cuvette is dissolution medium, 37 ℃ of water temperatures, rotating speed 50rmin, respectively at 0.5,1,1.5,2,3,6,12,24h syringe sampling 1ml, the drug release percentage ratio of each time point calculates with following formula:
Drug release percentage ratio (%)=(the tramadol original vol of sealing in amount/many vesicles liposome of free tramadol in the supernatant) * 100%
The result shows when the 3rd day (72 hours), drug release has reached more than 80%, the tramadol of sealing discharges (as shown in Figure 1) fully substantially, and conventional liposome just discharged fully at 12 hours, illustrated that the multivesicular liposomes of tramadol of the present invention has tangible slow release effect.
Experimental example 2: tramadol multivesicular liposome writhing method analgesic activity test
It is some to get Kunming mouse, and male and female half and half are divided into 3 groups at random, 10 every group.One group give normal saline in contrast (blank group), one group give tramadol injection (matched group) and one group to tramadol multivesicular liposome (test group), injection back 5min lumbar injection glacial acetic acid (0.6% glacial acetic acid injection volume is 0.2ml/10g) causes pain, observe animal and turn round the body situation, record cause respectively organize mice in the 15min of pain back turn round body number of times, result such as table 1.
Suppression ratio=(blank group mouse writhing number-matched group or test group mouse writhing number)/blank group mouse writhing number * 100%
Table 1 writhing method is surveyed tramadol multivesicular liposome is turned round the body number of times to the mice different time influence
With the blank group relatively, control group mice is turned round body and is counted to the 2nd, 3 day and change not obvious; Test group and control group mice turn round the body number of times reduce obviously (
*P＜0.05); Test group mouse writhing number of times reduced at the 2nd, 3 day more obviously (
*P＜0.01).
Experimental example 3: tramadol multivesicular liposome hot plate method analgesic activity test
It is some to get Kunming mouse, and male and female half and half are divided into 3 groups at random, 10 every group.Constant temperature shows water tank (55.0 ± 0.5) ℃, and each organizes mice medication before measurement pain 2 times, each 10 minutes at interval, gets its meansigma methods and be the basic threshold of pain (put into time of licking metapedes pain threshold as this Mus from mice, reject the threshold of pain greater than 30 seconds or less than 5 seconds mice).One group give normal saline in contrast (blank group), one group give tramadol multivesicular liposome (test group) for tramadol injection (matched group) and one group, and survey bitterly in injection back 5min.All survey pain 1 time later on, survey result such as table 2 altogether 4 times every 10min.
Table 2 hot plate method is surveyed the influence of tramadol multivesicular liposome to mice different time threshold of pain raising rate
Compare with the blank group, raising rate in the control group mice threshold of pain is counted to the 1st hour obvious difference; Test group and control group mice threshold of pain raising rate 12～24 hours obvious differences (
*P＜0.05); 48～72 hours difference of test group mouse writhing number of times more obviously (
*P＜0.01).
Claims (10)
1. the preparation method of a tramadol multivesicular liposome is characterized in that, may further comprise the steps:
1. phospholipid, cholesterol, the neutral lipid with natural or synthetic is dissolved in the organic solvent, as organic facies, wherein the molar concentration of phospholipid in organic facies is 5～50mmol/L, the molar concentration of neutral lipid in organic facies is 1～10mmol/L, and the mol ratio of phospholipid and cholesterol is 1: 2～4: 1;
2. be 10～500mmol/L with tramadol its concentration that makes soluble in water, as interior water;
3. water in the 2. middle gained of step is added in isopyknic organic facies, shear-mixed emulsifying makes the water-in-oil type colostrum;
4. dispose the Freamine of 1～100mmol/L, in the Freamine that configures, add surfactant that 0.1～9% the osmotic pressure account for its weight regulates material and/or 0.01%～10% as outside water, outer water is added the 3. first Ruzhong of water-in-oil type of middle preparation of step, mix and form W/O/W type emulsion, be W/O/W type emulsion, the volume ratio of wherein said outer water and water-in-oil type colostrum is 1: 1～10: 1;
5. the W/O/W type emulsion that obtains is added in the 4. middle Freamine that disposes of step, wherein the volume ratio of W/O/W type emulsion and Freamine is 3: 1～1: 3, feed nitrogen or carbon dioxide and dry up the organic solvent of removing in the emulsion, obtain the suspension of liposome;
6. the suspension of liposome is dissolved in 1～100 times of volume step 4. in the Freamine of configuration, centrifugal treating then, the supernatant that inclines is collected lower floor's liposome turbid liquor, tramadol multivesicular liposome.
2. the preparation method of tramadol multivesicular liposome as claimed in claim 1 is characterized in that: step 1. described in phospholipid be selected from lecithin, soybean phospholipid, hydrolecithin, dimyristoyl phosphatidyl choline, PHOSPHATIDYL ETHANOLAMINE, DOPE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidyl glycerols, the phosphatidyl glycerol one or more; Neutral lipid is selected from one or more in olein, glycerol trioleate, glyceryl laurate ester, decanoin, tricaprylin, 3-butyrine glyceride, the vitamin E; Organic solvent is selected from one or more in ether, chloroform, dichloromethane, ethanol, butanols, oxolane, the ethyl acetate; The aminoacid of step described in 4. is a kind of in L-arginine, L-lysine, serine or the Aspartic Acid, osmotic pressure adjusting material is one or more in glucose, mannitol or the sodium chloride, and surfactant is one or more in Tween 80, span 20 or the polyvinyl alcohol.
3. the preparation method of tramadol multivesicular liposome as claimed in claim 2, it is characterized in that: phospholipid is one or more in hydrolecithin, soybean phospholipid, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, the two palmityl phosphatidyl glycerols; Neutral lipid is a glycerol trioleate; Organic solvent is chloroform or ether-dichloromethane mixture, and the volume ratio of ether and dichloromethane is 1: 3～3: 1 in wherein said ether-dichloromethane mixture.
4. as the preparation method of claim 1,2 or 3 described tramadol multivesicular liposomes, it is characterized in that: also add charged lipoid in the organic facies of step in 1., the mol ratio of this charged lipoid and described phospholipid is 1: 1～1: 50.
5. the preparation method of tramadol multivesicular liposome as claimed in claim 4, it is characterized in that: described electrically charged lipoid is one or more in Phosphatidylserine, phosphatidic acid or the 18-amine., and the mol ratio of this lipoid and phospholipid is 1: 3～1: 20.
6. a tramadol multivesicular liposome is characterized in that, is prepared by following steps:
1. phospholipid, cholesterol, the neutral lipid with natural or synthetic is dissolved in the organic solvent, as organic facies, wherein the molar concentration of phospholipid in organic facies is 5～50mmol/L, the molar concentration of neutral lipid in organic facies is 1～10mmol/L, and phospholipid and cholesterol mol ratio are 1: 2～4: 1;
2. be 10～500mmol/L with tramadol its concentration that makes soluble in water, as interior water;
3. water in the 2. middle gained of step is added in isopyknic organic facies, shear-mixed emulsifying makes the water-in-oil type colostrum;
4. dispose the Freamine of 1～100mmol/L, in the Freamine that configures, add surfactant that 0.1～9% the osmotic pressure account for its weight regulates material and/or 0.01%～10% as outside water, outer water is added the 3. first Ruzhong of water-in-oil type of middle preparation of step, mix and form W/O/W type emulsion, be W/O/W type emulsion, the volume ratio of wherein said outer water and water-in-oil type colostrum is 1: 1～10: 1;
5. the W/O/W type emulsion that obtains is added in the 4. middle Freamine that disposes of step, wherein the volume ratio of W/O/W type emulsion and Freamine is 3: 1～1: 3, feed nitrogen or carbon dioxide and dry up the organic solvent of removing in the emulsion, obtain the suspension of liposome;
6. the suspension of liposome is dissolved in 1～100 times of volume step 4. in the Freamine of configuration, centrifugal treating then, the supernatant that inclines is collected lower floor's liposome turbid liquor, tramadol multivesicular liposome.
7. tramadol multivesicular liposome as claimed in claim 6 is characterized in that: step 1. described in phospholipid be selected from lecithin, soybean phospholipid, hydrolecithin, dimyristoyl phosphatidyl choline, PHOSPHATIDYL ETHANOLAMINE, DOPE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, two palmityl phosphatidyl glycerols, the phosphatidyl glycerol one or more; Neutral lipid is selected from one or more in olein, glycerol trioleate, glyceryl laurate ester, decanoin, tricaprylin, 3-butyrine glyceride, the vitamin E; Organic solvent is selected from one or more in ether, chloroform, dichloromethane, ethanol, butanols, oxolane, the ethyl acetate; The aminoacid of step described in 4. is a kind of in L-arginine, L-lysine, serine or the Aspartic Acid, osmotic pressure adjusting material is one or more in glucose, mannitol or the sodium chloride, and surfactant is one or more in Tween 80, span 20 or the polyvinyl alcohol.
8. tramadol multivesicular liposome as claimed in claim 7 is characterized in that: phospholipid is one or more in hydrolecithin, soybean phospholipid, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dioleoyl phospholipid phatidylcholine, the two palmityl phosphatidyl glycerols; Neutral lipid is a glycerol trioleate; Organic solvent is chloroform or ether-dichloromethane mixture, and the volume ratio of ether and dichloromethane is 1: 3～3: 1 in wherein said ether-dichloromethane mixture.
9. as claim 6,7 or 8 described tramadol multivesicular liposomes, it is characterized in that: also add charged lipoid in the organic facies of step in 1., this charged lipoid is 1: 1～1: 50 with the mol ratio ratio of described phospholipid.
10. tramadol multivesicular liposome as claimed in claim 9 is characterized in that: described electrically charged lipoid is one or more in Phosphatidylserine, phosphatidic acid or the 18-amine., and this lipoid is 1: 3～1: 20 with the mol ratio ratio of phospholipid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010118394 CN101780039A (en) | 2010-03-05 | 2010-03-05 | Tramadol multivesicular liposome and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010118394 CN101780039A (en) | 2010-03-05 | 2010-03-05 | Tramadol multivesicular liposome and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101780039A true CN101780039A (en) | 2010-07-21 |
Family
ID=42520270
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010118394 Pending CN101780039A (en) | 2010-03-05 | 2010-03-05 | Tramadol multivesicular liposome and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101780039A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619149A (en) * | 2017-01-23 | 2017-05-10 | 上海应用技术大学 | Method for preparing nicotinamide-coated multivesicular liposomes |
| CN106726642A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of preparation method of many vesicles for coating OPC |
| CN106726641A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of many vesicles of cladding D panthenols and preparation method thereof |
| CN106726640A (en) * | 2017-01-19 | 2017-05-31 | 上海应用技术大学 | Ascorbic many vesicles of one kind cladding and preparation method thereof |
| CN106726643A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of many vesicles for coating water-soluble glabridin and preparation method thereof |
| CN106924185A (en) * | 2017-03-29 | 2017-07-07 | 烟台大学 | A kind of preparation method of the multivesicular liposome for being loaded with vesica |
| CN108324958A (en) * | 2018-05-17 | 2018-07-27 | 陕西师范大学 | A kind of preparation method of purpurine 18- liposome nano vesicles and the application in preparing for tumor |
| CN108669213A (en) * | 2018-04-26 | 2018-10-19 | 天津大学 | A kind of nisin thermal sensitive liposomes and its preparation method and application |
| CN110624099A (en) * | 2018-06-21 | 2019-12-31 | 深圳翰宇药业股份有限公司 | Glatiramer acetate multivesicular liposome and preparation method thereof |
| CN113976052A (en) * | 2021-11-03 | 2022-01-28 | 健进制药有限公司 | Preparation system and preparation method of multivesicular liposome |
| CN115067460A (en) * | 2022-06-16 | 2022-09-20 | 南京林业大学 | Red date pigment nano-particles and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642532A (en) * | 2002-03-22 | 2005-07-20 | 西拉格股份公司 | Sustained release formulation of tramadol |
| CN101467956A (en) * | 2007-12-25 | 2009-07-01 | 上海医药工业研究院 | Tramadol lipidosome gel for nose as well as preparation method and application thereof |
| CN101040853B (en) * | 2006-03-22 | 2010-05-12 | 上海医药工业研究院 | Bulleyaconitine multilocular liposomes and the method of preparing the same |
-
2010
- 2010-03-05 CN CN 201010118394 patent/CN101780039A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642532A (en) * | 2002-03-22 | 2005-07-20 | 西拉格股份公司 | Sustained release formulation of tramadol |
| CN101040853B (en) * | 2006-03-22 | 2010-05-12 | 上海医药工业研究院 | Bulleyaconitine multilocular liposomes and the method of preparing the same |
| CN101467956A (en) * | 2007-12-25 | 2009-07-01 | 上海医药工业研究院 | Tramadol lipidosome gel for nose as well as preparation method and application thereof |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106726640A (en) * | 2017-01-19 | 2017-05-31 | 上海应用技术大学 | Ascorbic many vesicles of one kind cladding and preparation method thereof |
| CN106726642A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of preparation method of many vesicles for coating OPC |
| CN106726641A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of many vesicles of cladding D panthenols and preparation method thereof |
| CN106726643A (en) * | 2017-01-23 | 2017-05-31 | 上海应用技术大学 | A kind of many vesicles for coating water-soluble glabridin and preparation method thereof |
| CN106619149A (en) * | 2017-01-23 | 2017-05-10 | 上海应用技术大学 | Method for preparing nicotinamide-coated multivesicular liposomes |
| CN106924185A (en) * | 2017-03-29 | 2017-07-07 | 烟台大学 | A kind of preparation method of the multivesicular liposome for being loaded with vesica |
| CN106924185B (en) * | 2017-03-29 | 2019-11-26 | 烟台大学 | A kind of preparation method for the multivesicular liposome being loaded with vesica |
| CN108669213B (en) * | 2018-04-26 | 2021-06-08 | 天津大学 | Nisin thermosensitive liposome and preparation method and application thereof |
| CN108669213A (en) * | 2018-04-26 | 2018-10-19 | 天津大学 | A kind of nisin thermal sensitive liposomes and its preparation method and application |
| CN108324958A (en) * | 2018-05-17 | 2018-07-27 | 陕西师范大学 | A kind of preparation method of purpurine 18- liposome nano vesicles and the application in preparing for tumor |
| CN108324958B (en) * | 2018-05-17 | 2021-09-24 | 陕西师范大学 | Preparation method of purpurin 18-liposome nano-vesicles and application of purpurin 18-liposome nano-vesicles in preparation of drugs for treating tumors |
| CN110624099A (en) * | 2018-06-21 | 2019-12-31 | 深圳翰宇药业股份有限公司 | Glatiramer acetate multivesicular liposome and preparation method thereof |
| CN113976052A (en) * | 2021-11-03 | 2022-01-28 | 健进制药有限公司 | Preparation system and preparation method of multivesicular liposome |
| CN115067460A (en) * | 2022-06-16 | 2022-09-20 | 南京林业大学 | Red date pigment nano-particles and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101780039A (en) | Tramadol multivesicular liposome and preparation method thereof | |
| JP4885715B2 (en) | Irinotecan formulation | |
| CN102271659B (en) | Liposome of irinotecan or its hydrochloride and preparation method thereof | |
| CA2267416C (en) | Method for producing liposomes with increased percent of compound encapsulated | |
| CN103370055B (en) | Long-lasting controlled-release liposome composition and method for producing same | |
| CN103494773B (en) | A kind of ZL006 liposome and preparation method thereof | |
| WO2010041256A2 (en) | A composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same | |
| JP2009513621A (en) | Method for preparing liposomes and use thereof | |
| WO2010009186A1 (en) | Liposome formulation having hydrophilic and hydrophobic pharmaceutical compounds co-encapsulated therein | |
| CN103120645A (en) | Irinotecan or irinotecan hydrochloride lipidosome and preparation method thereof | |
| CA2570329C (en) | Liposome preparation containing slightly water-soluble camptothecin | |
| CN101536981B (en) | Clonidine hydrochloride multivesicular liposome and preparation method thereof | |
| CN101040853B (en) | Bulleyaconitine multilocular liposomes and the method of preparing the same | |
| PL183104B1 (en) | Selegillin containing liposome-based composition | |
| JPWO2010058840A1 (en) | Drug release means from liposome and evaluation method for release | |
| CN101756902B (en) | Clonidine multivesicular liposome and preparation method thereof | |
| CN102274182B (en) | Multivesicular liposome containing exenatide, preparation method and application thereof | |
| CN101190183B (en) | Clonidine hydrochloride multi-vesicular liposome and preparation method thereof | |
| CN101244040B (en) | Dioscorea opposita saponin liposome, method for preparing its preparations and uses thereof | |
| JPH11171772A (en) | Liposome preparation of antitumor medicine | |
| CN101744765B (en) | Bulleyaconitine A multivesicular liposome and preparation method thereof | |
| CN113116823A (en) | Liposome and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100721 |